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. 2021 Mar 23;16(3):e0249090. doi: 10.1371/journal.pone.0249090

Magnitude of asymptomatic COVID-19 cases throughout the course of infection: A systematic review and meta-analysis

Muluneh Alene 1,*, Leltework Yismaw 1, Moges Agazhe Assemie 1, Daniel Bekele Ketema 1, Belayneh Mengist 1, Bekalu Kassie 2, Tilahun Yemanu Birhan 3
Editor: Kin On Kwok4
PMCID: PMC7987199  PMID: 33755688

Abstract

Background

Asymptomatic SARS-CoV-2 infections are responsible for potentially significant transmission of COVID-19. Worldwide, a number of studies were conducted to estimate the magnitude of asymptomatic COVID-19 cases. However, there is a need for more robust and well-designed studies to have a relevant public health intervention. Synthesis of the available studies significantly strengthens the quality of evidences for public health practice. Thus, this systematic review and meta-analysis aimed to determine the overall magnitude of asymptomatic COVID-19 cases throughout the course of infection using available evidences.

Methods

We followed the PRISMA checklist to present this study. Two experienced review authors (MA and DBK) were systematically searched international electronic databases for studies. We performed meta-analysis using R statistical software. The overall weighted proportion of asymptomatic COVID-19 cases throughout the course infection was computed. The pooled estimates with 95% confidence intervals were presented using forest plot. Egger’s tests were used to assess publication bias, and primary estimates were pooled using a random effects model. Furthermore, a sensitivity analysis was conducted to assure the robustness of the result.

Results

A total of 28 studies that satisfied the eligibility criteria were included in this systematic review and meta-analysis. Consequently, in the meta-analysis, a total of 6,071 COVID-19 cases were included. The proportion of asymptomatic infections among the included studies ranged from 1.4% to 78.3%. The findings of this meta-analysis showed that the weighted pooled proportion of asymptomatic COVID-19 cases throughout the course of infection was 25% (95%CI: 16–38). The leave-one out result also revealed that the weighted pooled average of asymptomatic SARS-CoV-2 infection was between 28% and 31.4%.

Conclusions

In conclusion, one-fourth of SARS-CoV-2 infections are remained asymptomatic throughout the course infection. Scale-up of testing, which targeting high risk populations is recommended to tackle the pandemic.

Background

The novel coronavirus disease 2019 (“COVID-19”) caused by sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now established a global pandemic [1]. The pandemic is a challenge for both developed and developing countries causing huge stress on the healthcare system of all countries [2]. Up to February 20, 2021; there were more-than 110 million total COVID-19 cases with more-than two million deaths, worldwide [3]. As studies reported, the early sign of the COVID-19 is pneumonia [4]. In addition, of COVID-19 patients who developed signs and symptoms, the most frequently reported symptoms was fever followed by cough [5].

Asymptomatic and presymptomatic COVID-19 cases are responsible for potentially significant transmissions, and this makes a challenge to control the pandemic [6]. Approximately, half of individuals with positive test results don’t have any symptoms at the time of testing [7]. Additionally, about one-fifth of SARS-CoV-2 infections are remained asymptomatic throughout the course infection. One study indicated that the viral shedding coronavirus is peaked on before symptom onset [8]. This indicates that a substantial proportion of transmission probably occurred before first symptoms in the primary case. Another studies conducted in Singapore and China revealed that about 6.4%, and 12.6% of COVID-19 cases were attributed to asymptomatic transmission, respectively. Consequently, asymptomatic transmission expected to occur 1–3 days before symptom onset of source patients [9].

The serial interval and incubation period are the two main epidemiological parameters that suggests for presymptomatic transmission of COVID-19. When the average serial interval of COVID-19 is shorter than the average incubation period, some proportion of cases are attributed to presymptomatic transmission [10]. Accordingly, an observational study which aimed to provide the epidemiological parameters of COVID-19 using seven countries data revealed that the mean incubation period and serial interval were 7.44 days and 6.70 days, respectively [11].

Globally, a number of studies were conducted to determine the magnitude of asymptomatic SARS-CoV-2 infection. However, there is a need for more robust and well-designed studies to have relevant public health intervention. Studies vary depending on the number of participants recruited, the type of design employed and the country in which the study conducted [12, 13]. Combined findings of existing studies significantly strengthen the quality of evidences for public health practice. Since the biological, clinical and epidemiological characteristics of COVID-19 didn’t well known, this well design and appropriately performed study is needed to have a solid evidence-based intervention. The findings of this study will have a potential role to inform policymakers and stakeholders to combat the pandemic. Thus, this systematic review and meta-analysis aims to determine the pooled magnitude of asymptomatic COVID-19 cases throughout the course of infection using existing evidences.

Methods

Searching for studies

The study follows the preferred reporting items for systematic review and meta-analysis (PRISMA) to present this study. The search was done by two experienced review authors (MA and MAA) from international electronic databases (Google Scholar, PubMed, Science Direct, Web of Science, and CINAHL). In addition, we searched from the reference lists of the included studies to identify any other studies that may have been missed by our search strategy. We used the following search terms: “magnitude” OR “prevalence” AND “asymptomatic” OR “presymptomatic” OR “silent” AND “transmission” AND “coronavirus OR “COVID-19” OR “novel coronavirus” OR “SARS-CoV-2”. Our search was performed between the 1st of June and the 9th of December, 2020. Finally, all studies were imported into reference management software (Mendeley desktop).

Inclusion criteria

Estimates reported: all observational studies reported the magnitude of asymptomatic COVID-19 cases throughout the course of infection

Study setting: worldwide

Population: all age group

Publication status: all published, and unpublished articles

Language: only studies reporting using English language

Publication date: published from the 1st of January to the 9th of December, 2020

Exclusion criteria

Articles that was not report the outcome of interest, case reports and review studies were excluded.

Outcome variable and data extraction

The outcome variable of this study was the magnitude of true asymptomatic SARS-CoV-2 infection. Asymptomatic SARS-CoV-2 infection is defined as an individual without a history of clinical signs and symptoms throughout the course of infection. Two experienced review authors (MA and LY) extracted all essential data from the included studies using a predesigned data extraction form. The data extraction form organized as; the last name of the first author, the country of the study conducted, data collection period, sample size, magnitude of asymptomatic COVID-19 cases. Any inconsistencies in the data extraction process were decided through discussion involving all authors.

Quality assessment

Two review authors (LY and TYB) were assessed the risk of bias of the included articles. The Newcastle Ottawa Scale (NOS) adapted for cross-sectional studies was used to evaluate the quality of studies [14]. This tool organized from three major sections. Consequently, the first section scored on the basis of one to five stars focuses on the methodological quality of each study. The second segment of the tool evaluates the comparability of the study groups with a maximum possibility of two stars to be given. The last section of the tool is concerned with the outcomes and statistical analysis of the included studies with a maximum possibility of three stars to be given. Each author rated the quality of each article. Any inconsistent report between the two reviewers was decided by taking the average score of the two reviewers’. Finally, the assessed articles with a score of less than six out of ten were considered as achieving low quality.

Data processing and analysis

After extracting all essential data using Microsoft Excel, data were exported to R statistical software for further analysis. In-consistency among the reported magnitude of asymptomatic SARS-CoV-2 infection was assessed using I2-index [15]. To estimate the weighted pooled magnitude of asymptomatic COVID-19 cases, a random-effect meta-analysis with an estimation of DerSimonian and Laird method was performed. The publication bias was assessed using a tool known as a funnel plot. Funnel plot asymmetry was also tested by using Egger’s and Beggs’ tests [16]. Furthermore, leave-one-out meta-analysis was conducted to assure the robustness of the result. Leave-one-out analysis involves performing a meta-analysis on each subset of the studies obtained by leaving out exactly one study. This shows how each individual study affects the overall estimate of the rest of the studies.

Results

Search results

Fig 1, shows the flow chart diagram describing the selection of studies included in the systematic review and meta-analysis. Our search resulted with a total of 8,260 studies. Consequently, 134 articles were eligible for screening after excluding duplication. Ninety six articles were excluded after reading the title and abstract. After carefully assessed the text in the included studies, ten articles were removed due to not extractable result and the outcome of interest. Finally, in this study, we included a total of 28 studies that satisfied the eligibility criteria.

Fig 1. Flow chart diagram describing the selection of studies included in the systematic review and meta-analysis on the magnitude of truly asymptomatic SARS-CoV-2 infection, 2020.

Fig 1

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Description of the included studies

The detail description of the included studies are presented in (Table 1). In this systematic review and meta-analysis, a total of 28 studies with a total COVID-19 cases of 6,071 COVID-19 included. The smallest sample size was 23 [17], while the largest sample size was 712 [18]. Nearly half (48.3%) of the included studies were conducted from China.

Table 1. Descriptions of the included studies conducted on the proportion of asymptomatic SARS-CoV-2 infection, 2020.

No. First author Country Study period Total cases Asymptomatic cases
1. An et al [19] China April, 2020 * 25 16
2. Arons et al [20] USA March 13 to 20,2020 48 3
3. Chun et al [21] South Korea January 23 to March 31, 2020 89 16
4. Day et al [22] China April 1,2020 * 166 130
5. Feaster et al [23] USA April, 2020 * 631 257
6. Inui et al [24] Japan February 7 to 28,2020 104 76
7. Keeley et al [25] Argentina March, 2020 * 128 104
8. Kimball et al [17] USA March 13,2020 * 23 3
9. Kong et al [26] China January 25 to February 20,2020 511 100
10. Lavezzo et al [27] Italy February 23 to March 8, 2020 102 44
11. Ling et al [28] China January 23 to February 18, 2020 295 4
12. Long et al [29] China February 6, 2020 * 178 37
13. Luo et al [30] China February 21, 2020 * 83 8
14. Ma et al [31] China Jan 23 to March 10,2020 47 11
15. Meng et al [32] China Jan 1 and Feb 23, 2020 58 42
16. Mizumoto et al [33] Japan February 20,2020 * 634 328
17. Moriarty et al [18] Japan February to March 2020 712 331
18. Nishiura et al [34] Japan February 12, 2020 * 565 235
19. Noh et al [35] North Korea March, 2020 * 199 53
20. Rivett et al [36] United kingdom April, 2020 * 30 17
21. Tabata et al [37] Japan Feb 11 to Feb 25, 2020 104 33
22. Tian et al [38] China Feb 10, 2020 * 262 13
23. Wan et al [39] China February 20,2020 * 78 2
24. Wong et al [40] Brunei April 24, 2020 * 138 16
25. Xu et al [41] China January 18 to February 26, 2020 342 15
26. Zhao et al [42] China February 21,2020 * 160 4
27. Zhou et al [43] China March 4, 2020 * 328 10
28. Zhou et al [44] China Jan 23 to March 3,2020 31 9
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*study period was not clearly stated.

Magnitude of asymptomatic COVID-19 cases

Of the included studies, the proportion of asymptomatic SARS-CoV-2 infections ranged from 1% to 81%. Consequently, our meta-analysis showed that the weighted pooled truly asymptomatic COVID-19 cases was 25% (95%CI: 16–38) (Fig 2). Table 2, shows the sensitivity analysis of the study. The minimum weighted pooled proportion (28%) of SARS-CoV-2 was found by removing article [22], while the maximum proportion (31.4%) was obtained after removing the study [28]. The issue of publication bias was assessed by graphic inspection of funnel plot and using the rank correlation test. Even though, the funnel plot looks asymmetrical (Fig 3), the rank correlation test showed that no relationship between the effect size and its precision (P-value = 0.4).

Fig 2. Forest plot that shows the weighted pooled proportion of asymptomatic SARS-CoV-2 infection using available studies, 2020.

Fig 2

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Table 2. The sensitivity analysis to estimate the pooled proportion of truly asymptomatic SARS-CoV-2 infection, 2020.

No. Study omitted Pooled proportion (95%CI) No. Study omitted Pooled proportion (95%CI)
1. An et al 28.7 (18.9, 39.6) 15. Meng et al 28.4 (18.8,39.0)
2. Arons et al 28.9 (19.0, 39.9) 16. Mizumoto et al 30.3 (20.1,41.6)
3. Chun et al 30.3 (20.1,41.5) 17. Moriarty et al 29.2 (19.2,40.4)
4. Day et al 28 (18.6,38.5) 18. Nishiura et al 29.4 (19.3,40.6)
5. Feaster et al 29.4 (19.3,40.6) 19. Noh et al 30.0 (19.8,41.2)
6. Inui et al 28.3 (18.7,38.9) 20 Rivett et al 29.0 (19.1,39.9)
7. Keeley et al 27.9 (18.6,38.3) 21. Tabata et al 29.8 (19.6,41.0)
8. Kimball et al 29.1 (19.2,40.2) 22. Tian et al 31.1 (20.9,42.1)
9. Kong et al 30.3 (20.1,41.5) 23. Wan et al 31.2 (21.2,42.2)
10. Lavezzo et al 29.4 (19.3,40.5) 24. Wong et al 30.6 (20.5,41.8)
11. Ling et al 31.4 (21.5,42.5) 25. Xu et al 31.1 (21.1,42.1)
12. Long et al 30.2 (20.0,41.5) 26. Zhao et al 31.3 (21.3,42.2)
13. Luo et al 30.7 (20.6,41.9) 27. Zhou et al 31.2 (21.2,42.2)
14. Ma et al 30.1(19.9,41.3) 28. Zhou et al 29.8 (19.7,41.1)
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Fig 3. Funnel plot to check the publication bias of the included studies conducted on truly asymptomatic SARS-CoV-2 infection, 2020.

Fig 3

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Discussion

COVID-19 pandemic remains a major public health problem worldwide. Currently, there is no enough evidences to recommend any specific medication for the treatment of COVID-19. Presymptomatic and asymptomatic SARS-CoV-2 infections are capable to transmitting the virus, and this makes challenging to prevent and control the pandemic. Previous evidences showed that SARS-CoV-2 infections are spread more rapidly compared with Sever Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) [45]. Previous studies suggest that contact and symptom based screening might fail to identify all potential SARS-CoV-2 infections. The current study was aimed to determine the overall magnitude of asymptomatic COVID-19 cases throughout the course of infection.

We computed the overall weighted proportion of COVID-19 cases who hadn’t developed signs and symptoms throughout the course of infection. Accordingly, one-fourth (25% (95%CI: 16–38)) of COVID-19 cases were asymptomatic throughout the course of infection. This result is comparable with previous study conducted on the asymptomatic SARS-CoV-infections. However, this result is lower than previous studies conducted on asymptomatic SARS-CoV-2 infection [6, 7]. The possible reason for this variation might be asymptomatic COVID-19 cases considered in the previous studies will develop sign and symptoms during hospitalization period. A study conducted in Barcelona, Spain revealed that more-than two-third of SRAS-CoV-2 infections are asymptomatic at the time of testing [46].

We also compared the proportion of asymptomatic SARS-CoV-2 infections with previously emerged coronavirus outbreaks. A study that reports the role of asymptomatic patients in the transmission of MERS-CoV showed that one-fourth (25.1%) of MERS-CoV were asymptomatic [47]. Though, one study showed that small number of SARS-CoV cases are asymptomatic, unlike COVID-19, sever acute respiratory syndrome could be controlled by effective isolation of symptomatic patients [48]. One study also showed that nearly half of SARS-CoV patients were asymptomatic throughout the course hospitalization [49]. This inconsistency might be due to the difference in clinical severity between COVID-19 cases, MERS and SARS-CoV [50].

Limitation

The current study has a number of limitations. Firstly, the majority of the included studies had relatively small sample size which may decrease the power of the study. Secondly, the review was limited to only articles published in the English language. Lastly, since the included articles are limited to few countries, it may not represent the global figure of asymptomatic SARS-CoV-2 infection.

Conclusions

In conclusion, one-fourth of SARS-CoV-2 infections are remained asymptomatic throughout the course infection. Scale-up of testing, which targeting high risk populations is recommended to tackle the pandemic.

Supporting information

S1 Checklist. PRISMA 2009 checklist.

(DOC)

Click here for additional data file. (64.5KB, doc)
S1 Table. Individual effect sizes of the included studies conducted on truly asymptomatic SARS-CoV-2 infection, 2020.

(DOCX)

Click here for additional data file. (180.3KB, docx)

Abbreviations

COVID-19

The 2019 Novel Coronavirus Disease

MERS-CoV

Middle East respiratory syndrome coronavirus

SARS-CoV

Severe Acute Respiratory Syndrome Coronavirus

Sever SARS-CoV-2

Severe Acute Respiratory Syndrome Coronavirus 2

WHO

World Health Organization

CI

Confidence Interval

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

References

  • 1.WHO. media briefing on COVID-19–11 March 2020. Accessed from https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—11-march-2020.
  • 2.The world bank.The Global Economic Outlook During the COVID-19 Pandemic: A Changed World,June 8,2020. accessed from https://www.worldbank.org/en/news/feature/2020/06/08/the-global-economic-outlook-during-the-covid-19-pandemic-a-changed-world. [Google Scholar]
  • 3.JHONS HOPKINS coronavirus resource center.COVID-19. Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU).
  • 4.Rafiq D, Batool A, Bazaz MA. Three months of COVID‐19: A systematic review and meta‐analysis. Reviews in Medical Virology. 2020. May 18:e2113. 10.1002/rmv.2113 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Grant MC, Geoghegan L, Arbyn M, Mohammed Z, McGuinness L, Clarke EL, et al. The Prevalence of Symptoms in 24,410 Adults Infected by the Novel Coronavirus (SARS-CoV-2; COVID-19): A Systematic Review and Meta-Analysis of 148 Studies from 9 Countries. Avail. 10.1371/journal.pone.0234765 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Kronbichler A, Kresse D, Yoon S, Lee KH, Effenberger M, Shin JI. Asymptomatic patients as a source of COVID-19 infections: A systematic review and meta-analysis. International Journal of Infectious Diseases. 2020. June 17. 10.1016/j.ijid.2020.06.052 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Syangtan G, Bista S, Dawadi P, Rayamajhee B, Shrestha LB, Tuladhar R, et al. Asymptomatic people with SARS-CoV-2 as unseen carriers of COVID-19: A systematic review and meta-analysis. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.He X, Lau EH, Wu P, Deng X, Wang J, Hao X, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nature medicine. 2020. May;26(5):672–5. 10.1038/s41591-020-0869-5 [DOI] [PubMed] [Google Scholar]
  • 9.Wei WE, Li Z, Chiew CJ, Yong SE, Toh MP, Lee VJ. Presymptomatic Transmission of SARS-CoV-2—Singapore, January 23–March 16, 2020. Morbidity and Mortality Weekly Report. 2020. April 10;69(14):411. 10.15585/mmwr.mm6914e1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Du Z, Xu X, Wu Y, Wang L, Cowling BJ, Meyers LA. Serial interval of COVID-19 among publicly reported confirmed cases. Emerging infectious diseases. 2020. June;26(6):1341. 10.3201/eid2606.200357 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Ma S, Zhang J, Zeng M, Yun Q, Guo W, Zheng Y, et al. Epidemiological parameters of coronavirus disease 2019: a pooled analysis of publicly reported individual data of 1155 cases from seven countries. Medrxiv. 2020. January 1. [Google Scholar]
  • 12.Alene M, Yismaw L, Berelie Y, Kassie B, Yeshambel R, Assemie MA. Prevalence and determinants of unintended pregnancy in Ethiopia: A systematic review and meta-analysis of observational studies. PloS one. 2020. April 7;15(4):e0231012. 10.1371/journal.pone.0231012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Alene M, Assemie MA, Yismaw L, Gedif G, Ketema DB, Gietaneh W, et al. Patient delay in the diagnosis of tuberculosis in Ethiopia: a systematic review and meta-analysis. BMC infectious diseases. 2020. December;20(1):1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Newcastle-Ottawa Scale customized for cross-sectional studies In. available from https://static-content.springer.com/esm/…/12889_2012_5111_MOESM3_ESM.doc.
  • 15.Melsen WG, Bootsma MC, Rovers MM, Bonten MJ. The effects of clinical and statistical heterogeneity on the predictive values of results from meta-analyses. Clinical Microbiology and Infection. 2014. February 1;20(2):123–9. 10.1111/1469-0691.12494 [DOI] [PubMed] [Google Scholar]
  • 16.van Enst WA, Ochodo E, Scholten RJ, Hooft L, Leeflang MM. Investigation of publication bias in meta-analyses of diagnostic test accuracy: a meta-epidemiological study. BMC medical research methodology. 2014. December 1;14(1):70. 10.1186/1471-2288-14-70 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Kimball A, Hatfield KM, Arons M, James A, Taylor J, Spicer K, et al. Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled nursing facility—King County, Washington, March. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Moriarty LF. Public health responses to COVID-19 outbreaks on cruise ships—worldwide, February–March 2020. MMWR. Morbidity and mortality weekly report. 2020;69. 10.15585/mmwr.mm6912e3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.An P, Song P, Wang Y, Liu B. Asymptomatic patients with novel coronavirus disease (COVID-19). Blood. 2020. April 13;3:12–0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Arons MM, Hatfield KM, Reddy SC, Kimball A, James A, Jacobs JR, et al. Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility. New England journal of medicine. 2020. April 24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Chun JY, Baek G, Kim Y. Transmission onset distribution of COVID-19 in South Korea. medRxiv. 2020. January 1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. [DOI] [PubMed] [Google Scholar]
  • 23.Feaster M, Goh YY. High Proportion of Asymptomatic SARS-CoV-2 Infections in 9 Long-Term Care Facilities, Pasadena, California, USA, April 2020. Emerging Infectious Diseases. 2020. July 2;26(10). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Inui S, Fujikawa A, Jitsu M, Kunishima N, Watanabe S, Suzuki Y, et al. Chest CT findings in cases from the cruise ship “Diamond Princess” with coronavirus disease 2019 (COVID-19). Radiology: Cardiothoracic Imaging. 2020. March 17;2(2):e200110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Keeley AJ, Evans CM, De Silva TI. Asymptomatic SARS-CoV-2 infection: the tip or the iceberg?. Thorax. 2020. August 1;75(8):621–2. 10.1136/thoraxjnl-2020-215337 [DOI] [PubMed] [Google Scholar]
  • 26.Kong W, Wang Y, Hu J, Chughtai A, Pu H, of Sichuan CR. Comparison of clinical and epidemiological characteristics of asymptomatic and symptomatic SARS-CoV-2 infection: A multi-center study in Sichuan Province, China. Travel Medicine and Infectious Disease. 10.1016/j.tmaid.2020.101754 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Lavezzo E, Franchin E, Ciavarella C, Cuomo-Dannenburg G, Barzon L, Del Vecchio C, et al. Suppression of COVID-19 outbreak in the municipality of Vo, Italy. medRxiv. 2020. January 1. [Google Scholar]
  • 28.Ling Z, Xu X, Gan Q, Zhang L, Luo L, Tang X, et al. Asymptomatic SARS-CoV-2 infected patients with persistent negative CT findings. European journal of radiology. 2020. May 1;126. 10.1016/j.ejrad.2020.108956 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Long QX, Tang XJ, Shi QL, Li Q, Deng HJ, Yuan J, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nature medicine. 2020. June 18:1–5. 10.1038/s41591-020-0965-6 [DOI] [PubMed] [Google Scholar]
  • 30.Luo SH, Liu W, Liu ZJ, Zheng XY, Hong CX, Liu ZR, et al. A confirmed asymptomatic carrier of 2019 novel coronavirus. Chinese medical journal. 2020. May 5;133(9):1123–5. 10.1097/CM9.0000000000000798 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Ma Y, Xu QN, Wang FL, Ma XM, Wang XY, Zhang XG, et al. Characteristics of asymptomatic patients with SARS-CoV-2 infection in Jinan, China. Microbes and Infection. 2020. May 7. 10.1016/j.micinf.2020.04.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Meng H, Xiong R, He R, Lin W, Hao B, Zhang L, et al. CT imaging and clinical course of asymptomatic cases with COVID-19 pneumonia at admission in Wuhan, China. Journal of Infection. 2020. April 12. 10.1016/j.jinf.2020.04.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Mizumoto K, Kagaya K, Zarebski A, Chowell G. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Eurosurveillance. 2020. March 12;25(10):2000180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Nishiura H, Kobayashi T, Miyama T, Suzuki A, Jung SM, Hayashi K, et al. Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). International journal of infectious diseases. 2020. M. 10.1016/j.jebdp.2020.101499 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Noh JY, Yoon JG, Seong H, Choi WS, Sohn JW, Cheong HJ, et al. Asymptomatic infection and atypical manifestations of COVID-19: comparison of viral shedding duration. The Journal of Infection. 2020. May 21. 10.1016/j.jinf.2020.05.035 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Rivett L, Sridhar S, Sparkes D, Routledge M, Jones NK, Forrest S, et al. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission. Elife. 2020. M. 10.7554/eLife.58728 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Tabata S, Imai K, Kawano S, Ikeda M, Kodama T, Miyoshi K, et al. Clinical characteristics of COVID-19 in 104 people with SARS-CoV-2 infection on the Diamond Princess cruise ship: a retrospective analysis. The La. 10.1016/S1473-3099(20)30482-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Tian S, Hu N, Lou J, Chen K, Kang X, Xiang Z, et al. Characteristics of COVID-19 infection in Beijing. Journal of Infection. 2020. February 27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Wan R, Mao ZQ, He LY, Hu YC. Evidence from two cases of asymptomatic infection with SARS-CoV-2: Are 14 days of isolation sufficient?. International Journal of Infectious Diseases. 2020. June 1;95:174–5. 10.1016/j.ijid.2020.03.041 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Wong J, Abdul Aziz AB, Chaw L, Mahamud A, Griffith MM, Ying-Ru LO, et al. High proportion of asymptomatic and presymptomatic COVID-19 infections in travelers and returning residents to Brunei. Journal of Travel Medicine. 2020. May 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Xu T, Huang R, Zhu L, Wang J, Cheng J, Zhang B, et al. Epidemiological and clinical features of asymptomatic patients with SARS‐CoV‐2 infection. Journal of medical virology. 2020. April 28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Zhao D, Wang M, Wang M, Zhao Y, Zheng Z, Li X, et al. Asymptomatic infection by SARS-CoV-2 in healthcare workers: a study in a large teaching hospital in Wuhan, China. International Journal of Infectious Diseases. 2020. August 3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Zhou X, Li Y, Li T, Zhang W. Follow-up of asymptomatic patients with SARS-CoV-2 infection. Clinical Microbiology and Infection. 2020. March 28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Zhou R, Li F, Chen F, Liu H, Zheng J, Lei C, et al. Viral dynamics in asymptomatic patients with COVID-19. Int J Infect Dis. 2020. May 11;96:288–90. 10.1016/j.ijid.2020.05.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Peeri NC, Shrestha N, Rahman MS, Zaki R, Tan Z, Bibi S, et al. The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned?. Internationa. 10.1093/ije/dyaa033 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Borras-Bermejo B, Martínez-Gómez X, San Miguel MG, Esperalba J, Antón A, Martin E, et al. Asymptomatic SARS-CoV-2 Infection in Nursing Homes, Barcelona, Spain, April 2020. Emerging Infectious Diseases. 2020. Ju. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Al-Tawfiq JA, Gautret P. Asymptomatic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection: extent and implications for infection control: a systematic review. Travel medicine and infectious disease. 2019. January 1;27:27–32. 10.1016/j.tmaid.2018.12.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Fraser C, Riley S, Anderson RM, Ferguson NM. Factors that make an infectious disease outbreak controllable. Proceedings of the National Academy of Sciences. 2004. April 20;101(16):6146–51. 10.1073/pnas.0307506101 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Chan PK, Ip M, Ng KC, Chan RC, Wu A, Lee N, et al. Severe acute respiratory syndrome–associated coronavirus infection. Emerging infectious diseases. 2003. November;9(11):1453. 10.3201/eid0911.030421 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Petrosillo N, Viceconte G, Ergonul O, Ippolito G, Petersen E. COVID-19, SARS and MERS: are they closely related?. Clinical Microbiology and Infection. 2020. March 28. [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Kin On Kwok

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

30 Oct 2020

PONE-D-20-28251

Magnitude of asymptomatic COVID-19 cases throughout the course of infection: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Muluneh Alene Addis,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Dec 12 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Kin On Kwok, Ph.D

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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2. Please confirm that you have included all items recommended in the PRISMA checklist including the full electronic search strategy used to identify studies with all search terms and limits for at least one database. Please attach a Supplemental file of the results of the individual components of the quality assessment, not just the overall score, for each study included. See https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1000100#pmed-1000100-t003 for guidance. Thank you.

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Additional Editor Comments (if provided):

This article aims to assess the magnitude of asymptomatic and pre-symptomatic COVID-19 cases which is essential and currently relevant for COVID-19 pandemic. Search terms may need to be refined to include as many as articles in the initial search. Will the authors consider to have pooled estimate stratified by age, setting such as hospital or community and study period to enrich the content. Also the exclusion criteria was not explicit mentioned. In terms of the language, authors are suggested to have substantial edit to arrive at the publishable quality.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Background

- Severe Acute Respiratory Syndrome Corn babirusa 2, instead of Sever respiratory syndrome Coronavirus 2

- This systematic review and meta-analysis aims to determine the pooled magnitude of asymptomatic COVID-19 cases throughout the course of infection? What about total cases, pre-symptomatic cases? The course of infection or the course of outbreak?

Method

- Additional search terms: cases, incidence, proportion, incubation period, serial interval

- Systematic review does not only include observational studies

- Study setting: worldwide? At hospital? At community?

- Population: All age group? Please provide age range.

- Publication status: I would not include unpublished articles

- Exclusion criteria: Not clear. Please explain.

- Outcome variable and data extraction: Please provide more details on the “predestined data extraction form”. The 1st section: How to assess the methodological quality of each study? The 2nd section: How to evaluate the comparability of the study group? The 3rd section: How to assess the outcome and statistical analysis?

Results

- What about incubation period and serial interval?

- please explain how to perform sensitivity analysis

Reviewer #2: Assessing the magnitude of asymptomatic and pre-symptomatic COVID-19 cases is important and currently relevant for COVID-19 pandemic over social and economic impacts.

Authors have here taken up a systematic review and meta-analysis on asymptomatic and pre-symptomatic and claimed symptom-based screening might fail to identify all potential SARS-CoV-2 infections. Finally, authors suggested to scale-up mass testing and targeting high risk populations to tackle the pandemic.

I anticipate that authors will be further address the suggested issue, mentioned below to improve the manuscript and its understanding to a broad readership.

1. Page-3: “Up to date, there are more than 22 million total cases with 780,000 deaths, worldwide (3).”, “Up to date” is not a right phrase to use here. Provide specific date of extracting data instead. Also, suggest to revise it as the study reporting the digits from long back in July, 2020.

2. Page-3: “Studies vary depending on the number of study participants recruited, the type of design employed and the country in which the study conducted.”, The sentence is not clear enough. What is the meaning of “the number of study participants recruited”? Need to revise the sentence for clarity. Further authors used the terms “Studies vary”, but not clearly mentioned in what context.

3. Page-3: Continuation of point 2 above, author need to present the research potential and motivation of the such review study in this paragraph before mentioning the objectives. Though author has mentioned the combining the exiting finding might strengthen the evidence.

4. Page-4: “In addition, we searched from the reference lists of the included studies to identify any other studies that may have been missed by our search strategy.”, I fell such statement is redundant as it’s a part of the review when reviewers need to assess the main text along with the title and abstract.

5. Page-4: “Our search was performed between the 1st of June and the 15th of July, 2020.”, the review time window is much backdated. Possibly suggest to update the time window to catch more data.

6. Page-4: “Inclusion criteria”, the term ‘Design’ is not really referring the design of the reviewed studies, instead it’s the outcome variable for which the review is subject to. It preferably better of mentioning “Estimates/ Estimates reported” instead of “Design”? Else clarify.

7. Page-4: “Exclusion criteria” need to mention clearly. Current form is not conveying what author wanted to mention. Need more detailed criteria.

8. Page-4: “Two experienced authors (MA and LY) extracted all essential data from the included studies using a predesigned data extraction form.”, hope these two review author did the search independently. If yes, please mention it else no need to mention specifically in the text. Independent search one if the tools to ensure the reproducibility of the results.

9. Page-5: “In addition, 10 articles were removed due to not extractable result and the outcome of interest not reported.”, This 10 studies were excluded after assessing the related “Text” of the articles. Need to be clearly mention it, as mentioned similarly for “titles and abstracts”.

10. Page-6: Table 1, “Study period” is not mentioned clearly for some of the studies. Need to clearly have a note for this in the table. Wonder, is it due to the missing information in the text.

11. Page-7: Author presented the magnitudes of ‘asymptomatic’ COVID-19 cases, wonder if it is included the ‘pre-symptomatic’ cases as well. Need clarification. Accordingly, the title of the manuscript should be revised.

12. Page-9: “We also compared the proportion of asymptomatic SARS-CoV-2 infections with previously emerged coronavirus pandemics.”, I wonder whether the MERS was a Pandemic? Otherwise, better to be specific by using ‘pandemics/epidemics’ or just simply ‘outbreaks”.

13. Page-9-10: “The result of this study suggest that contact and symptom based screening might fail to identify all potential SARS-CoV-2 infections.”, Author clamed this without any discussion in the main text on it. I would prefer to illustrate this in the discussion section first with the results and then suggest in the conclusion. Conclusion should be related to the results, otherwise take-home massage will be weaker to the readers.

14. Page-9-10: “Scale-up mass testing, which targeting high risk populations is recommended to tackle the pandemic. Continuation of the above points, ‘mass testing’ and ‘testing of the target high risk group’ are two different things. Prefer to revise or rearrange the sentence here.

15. Many of the references were in preprint now published should be updated.

16. The references are not according to the PloS One specification (“Vancouver” style). Need to be updated.

17. Finally, I would suggest to the authors to give some effort in the presentation and language of the manuscript to avoid the redundancy of text and improve the language for general readers.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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PLoS One. 2021 Mar 23;16(3):e0249090. doi: 10.1371/journal.pone.0249090.r002

Author response to Decision Letter 0

14 Dec 2020

Author's response to reviews

Title: Magnitude of asymptomatic COVID-19 cases throughout the course of infection: a systematic review and meta-analysis

Author’s email addresses

MA: mulunehadis@gmail.com

LY: lielt.yismaw@gmail.com

MAA: agazhemoges@gmail.com

DBK: danibekele2009@gmail.com

BM: Belaynehmengist2008@gmail.com

BK: bekalukassiedmu@gmail.com

TYB: yemanu.tilahun@gmail.com

Date: 12 December 2020

Dear Editor,

We thank you for the chance to resubmit our revised version of the manuscript. Also, we would like to thank the reviewers for sharing their view and experience. The comments are very important that will improve the manuscript. The point-by-point responses for each of the comments are provided in the following pages. We hope that the revisions meet your standards and that the paper would be published in your journal. We look forward to working with you towards a final published product.

Sincerely,

Muluneh Alene, MPH

On behalf of co-authors

Point by point responses to queries

Editor comments and suggestions

This article aims to assess the magnitude of asymptomatic and pre-symptomatic COVID-19 cases which is essential and currently relevant for COVID-19 pandemic. Search terms may need to be refined to include as many as articles in the initial search. Will the authors consider to have pooled estimate stratified by age, setting such as hospital or community and study period to enrich the content. Also the exclusion criteria was not explicit mentioned. In terms of the language, authors are suggested to have substantial edit to arrive at the publishable quality.

Response

Thank you dear editor for your constructive comments and suggestions. In the revised version of the manuscript, we already refined the searching terms in order to include the existing potential studies. Unfortunately, the original studies were not report the magnitude of asymptomatic COVID-19 cases by age. Additionally, all studies included in this review are facility-based. We try to write the manuscript in acceptable quality of English language.

Reviewer#1

Comments/suggestions #1

Severe Acute Respiratory Syndrome Corn babirusa 2, instead of Sever respiratory syndrome Coronavirus 2

Response#1

Thank you dear reviewer for your constructive suggestion and comments. The comments are very important to improve the manuscript. We used the standard WHO name of the novel coronavirus (Sever respiratory syndrome Coronavirus 2).

Comments/suggestions #2

This systematic review and meta-analysis aims to determine the pooled magnitude of asymptomatic COVID-19 cases throughout the course of infection? What about total cases, pre-symptomatic cases? The course of infection or the course of outbreak?

Response#2

Thank you. The scope (objective) of this study was to determine the overall magnitude of asymptomatic COVID-19 cases throughout the course of infection using available evidences. In this review, we only consider patients who are asymptomatic (without sign and symptoms) in the course of infection, not outbreak.

Comments/suggestions #3

-Systematic review does not only include observational studies

- Study setting: worldwide? At hospital? At community?

- Population: All age group? Please provide age range.

- Publication status: I would not include unpublished articles

- Exclusion criteria: Not clear. Please explain.

- Outcome variable and data extraction: Please provide more details on the “predestined data extraction form”. The 1st section: How to assess the methodological quality of each study? The 2nd section: How to evaluate the comparability of the study group? The 3rd section: How to assess the outcome and statistical analysis?

Response#3

Thank you. We considered your comments and suggestions. We understand that systematic review and meta-analysis is not only for observational studies, but also it is applicable for experimental studies. However, in this study, we only consider observational articles. In addition, articles included in this review were facility-based. No restriction in age group. Furthermore, studies included in this systematic review were published and unpublished articles. Moreover, we revised the text in the section of exclusion criteria, outcome variable of the interest, and extraction form. Regarding, the quality assessment the following points are considered. 1) To assess the methodological quality of each study; we consider: representativeness of the sample, sample size, non-respondents, and ascertainment of the exposure (risk factor). 2) To evaluate the comparability of the study group; we consider: how studies control for the most important factor, and the study control for any additional factor.

3) To assess the outcome and statistical analysis; we consider: the statistical test used to analyze the data is clearly described and appropriate, and the measurement of the association is presented, including confidence intervals and the probability level.

Comments/suggestions #4

- What about incubation period and serial interval?

- Please explain how to perform sensitivity analysis

Response#4

Thank you. Incubation period is the time from infection occurred to the onset of signs and symptoms. Also, the serial interval is the time from illness onset in the primary case to illness onset in the secondary case. It also measured from pairs of cases with a clear infector–infectee relationship. In the revised version of the manuscript, we explained in detail how sensitivity analysis performed.

Reviewer#2

Comments/suggestions#1

Page-3: “Up to date, there are more than 22 million total cases with 780,000 deaths, worldwide.”, “Up to date” is not a right phrase to use here. Provide specific date of extracting data instead. Also, suggest to revise it as the study reporting the digits from long back in July, 2020.

Response #1

Dear reviewer, we thank you for your constructive comments and suggestions. The comments are very important to improve the manuscript. In the revised version of the manuscript, we provided the specific date with the current level COVID-19 cases and deaths.

Comments/suggestions#2

Page-3: “Studies vary depending on the number of study participants recruited, the type of design employed and the country in which the study conducted.” The sentence is not clear enough. What is the meaning of “the number of study participants recruited”? Need to revise the sentence for clarity. Further authors used the terms “Studies vary”, but not clearly mentioned in what context.

Response#2

Thank you. Yes, we learnt that the sentence needs revision, and we already revised it in the revised version of the manuscript. In other word “the number of study participants recruited” means the sample size for a particular study. In addition, we describe in detail that in what context study varies.

Comments/suggestions#3

Page-3: Continuation of point 2 above, author need to present the research potential and motivation of such review study in this paragraph before mentioning the objectives. Though author has mentioned the combining the exiting finding might strengthen the evidence.

Response#3

Thank you. We try to explain further the potential and motivation of this study, in the revised form of the manuscript.

Comments/suggestions#4

Page-4: “In addition, we searched from the reference lists of the included studies to identify any other studies that may have been missed by our search strategy.”, I fell such statement is redundant as it’s a part of the review when reviewers need to assess the main text along with the title and abstract.

Response#4

Thank you. We considered to revise it.

Comments/suggestions#5

Page-4: “Our search was performed between the 1st of June and the 15th of July, 2020.” the review time window is much backdated. Possibly suggest to update the time window to catch more data.

Response#5

Thank you. We already updated the searching time.

Comments/suggestions#6

Page-4: “Inclusion criteria”, the term ‘Design’ is not really referring the design of the reviewed studies, instead it’s the outcome variable for which the review is subject to. It preferably better of mentioning “Estimates/ Estimates reported” instead of “Design”? Else clarify.

Response#6

Based on the suggestion given, we mentioned “Estimates reported” instead of “Design”.

Comments/suggestions#7

Page-4: “Exclusion criteria” need to mention clearly. Current form is not conveying what author wanted to mention. Need more detailed criteria.

Response#7

In the revised version of the manuscript, we provided clearly the exclusion criteria of this study.

Comments/suggestions#8

Page-4: “Two experienced authors (MA and LY) extracted all essential data from the included studies using a predesigned data extraction form.” hope these two review author did the search independently. If yes, please mention it else no need to mention specifically in the text. Independent search one if the tools to ensure the reproducibility of the results.

Response#8

Thank you, we removed the name of the authors upon your suggestion.

Comments/suggestions#9

Page-5: “In addition, 10 articles were removed due to not extractable result and the outcome of interest not reported.” This 10 studies were excluded after assessing the related “Text” of the articles. Need to be clearly mention it, as mentioned similarly for “titles and abstracts”.

Response#9

In the revised manuscript, we explicitly mention the reason for excluding studies.

Comments/suggestions#10

Page-6: Table 1, “Study period” is not mentioned clearly for some of the studies. Need to clearly have a note for this in the table. Wonder, is it due to the missing information in the text.

Response#10

Thank you. Some original studies did not explicitly provided the study period (data collection period).

Comments/suggestions#11

Page-7: Author presented the magnitudes of ‘asymptomatic’ COVID-19 cases, wonder if it is included the ‘pre-symptomatic’ cases as well. Need clarification. Accordingly, the title of the manuscript should be revised.

Response#11

Thank you. The outcome of interest (objective) of this study was to estimate the pooled magnitudes of asymptomatic COVID-19 cases throughout the course infection. We will come on that with another article.

Comments/suggestions#12

Page-9: “We also compared the proportion of asymptomatic SARS-CoV-2 infections with previously emerged coronavirus pandemics.” I wonder whether the MERS was a Pandemic. Otherwise, better to be specific by using ‘pandemics/epidemics’ or just simply ‘outbreaks”.

Response#12

Thank you. We restated it.

Comments/suggestions#13

Page-9-10: “The result of this study suggest that contact and symptom based screening might fail to identify all potential SARS-CoV-2 infections.” Author clamed this without any discussion in the main text on it. I would prefer to illustrate this in the discussion section first with the results and then suggest in the conclusion. Conclusion should be related to the results, otherwise take-home massage will be weaker to the readers.

Response#13

Thank you. We already revised it.

Comments/suggestions#14

Page-9-10: “Scale-up mass testing, which targeting high risk populations is recommended to tackle the pandemic. Continuation of the above points, ‘mass testing’ and ‘testing of the target high risk group’ are two different things. Prefer to revise or rearrange the sentence here.

Response#14

Thank you. We already revised it.

Comments/suggestions#15

Many of the references were in preprint now published should be updated.

16. The references are not according to the PloS One specification (“Vancouver” style). Need to be updated.

Response#15

Thank you. We already updated the references according to the PLOS ONE requirement.

Comments/suggestions#16

Finally, I would suggest to the authors to give some effort in the presentation and language of the manuscript to avoid the redundancy of text and improve the language for general readers.

Response#16

Thank you dear reviewer. We try to write the manuscript in acceptable quality of English language.

Thank you!!!

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (27.7KB, docx)

Decision Letter 1

Kin On Kwok

22 Jan 2021

PONE-D-20-28251R1

Magnitude of asymptomatic COVID-19 cases throughout the course of infection: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Addis,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

As suggested by the reviewer number 2, the authors are recommended to improve the language for general readers.

Please submit your revised manuscript by Mar 08 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Kin On Kwok, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: Authors tried to revise the manuscript but unable to improve the manuscript adequately. I further suggest authors to make the text precise and continuous for readers’ interest. In fact, authors missed/ avoided some of the comments/suggestions to address, here I strongly suggest to take up these seriously and revise the text extensively. I added those in further comments below as “Comments/Suggestions on Response #xx in R1”.

###################

Reviewer#2

Comments/suggestions#1: Page-3: “Up to date, there are more than 22 million total cases with 780,000 deaths, worldwide.”, “Up to date” is not a right phrase to use here. Provide specific date of extracting data instead. Also, suggest to revise it as the study reporting the digits from long back in July, 2020.

Response #1: Dear reviewer, we thank you for your constructive comments and suggestions. The comments are very important to improve the manuscript. In the revised version of the manuscript, we provided the specific date with the current level COVID-19 cases and deaths.

Comments/Suggestions on Response #1 in R1: Response and revision acceptable.

Comments/suggestions#2: Page-3: “Studies vary depending on the number of study participants recruited, the type of design employed and the country in which the study conducted.” The sentence is not clear enough. What is the meaning of “the number of study participants recruited”? Need to revise the sentence for clarity. Further authors used the terms “Studies vary”, but not clearly mentioned in what context.

Response#2: Thank you. Yes, we learnt that the sentence needs revision, and we already revised it in the revised version of the manuscript. In other word “the number of study participants recruited” means the sample size for a particular study. In addition, we describe in detail that in what context study varies.

Comments/Suggestions on Response #2 in R1: Still text needs to be revised. Please simplify as “Studies vary depending on the number of participants recruited, the type of design employed and the country in which the study conducted.”

Comments/suggestions#3: Page-3: Continuation of point 2 above, author need to present the research potential and motivation of such review study in this paragraph before mentioning the objectives. Though author has mentioned the combining the exiting finding might strengthen the evidence. Response#3 Thank you. We try to explain further the potential and motivation of this study, in the revised form of the manuscript.

Comments/Suggestions on Response #3 in R1: I was expecting more on motivations here. Specially to indicate why authors took up this study.

Comments/suggestions#4: Page-4: “In addition, we searched from the reference lists of the included studies to identify any other studies that may have been missed by our search strategy.”, I fell such statement is redundant as it’s a part of the review when reviewers need to assess the main text along with the title and abstract.

Response#4: Thank you. We considered to revise it.

Comments/Suggestions on Response #4 in R1: What are the revision here? It was just a suggestion. If you want to keep the sentence, no problem, still make sense. But could not understand what revision has been made in this context as claimed by author in revised version?

Comments/suggestions#5: Page-4: “Our search was performed between the 1st of June and the 15th of July, 2020.” the review time window is much backdated. Possibly suggest to update the time window to catch more data.

Response#5: Thank you. We already updated the searching time.

Comments/Suggestions on Response #5 in R1: Response and revision acceptable.

Comments/suggestions#6: Page-4: “Inclusion criteria”, the term ‘Design’ is not really referring the design of the reviewed studies, instead it’s the outcome variable for which the review is subject to. It preferably better of mentioning “Estimates/ Estimates reported” instead of “Design”? Else clarify.

Response#6: Based on the suggestion given, we mentioned “Estimates reported” instead of “Design”.

Comments/Suggestions on Response #6 in R1: Response and revision acceptable.

Comments/suggestions#7: Page-4: “Exclusion criteria” need to mention clearly. Current form is not conveying what author wanted to mention. Need more detailed criteria.

Response#7: In the revised version of the manuscript, we provided clearly the exclusion criteria of this study.

Comments/Suggestions on Response #7 in R1: Still not clear. Authors should not use the subjective term ‘fully’ here. What did the authors mean by ‘fully’?

Comments/suggestions#8: Page-4: “Two experienced authors (MA and LY) extracted all essential data from the included studies using a predesigned data extraction form.” hope these two review author did the search independently. If yes, please mention it else no need to mention specifically in the text. Independent search one if the tools to ensure the reproducibility of the results.

Response#8: Thank you, we removed the name of the authors upon your suggestion.

Comments/Suggestions on Response #8 in R1: Not sure, whether I was able to convey the issue to the authors by the comment? Removing the authors’ names were not the suggestion. Here I wanted to know whether two authors had performed the data extraction from the studies included independently or not? Generally, in systematic review and metanalysis the two (or more) authors performed such data extraction independently to ensure the reproducibility. Further, how did the authors settled the mismatches? should be clearly mentioned in the text.

Comments/suggestions#9: Page-5: “In addition, 10 articles were removed due to not extractable result and the outcome of interest not reported.” This 10 studies were excluded after assessing the related “Text” of the articles. Need to be clearly mention it, as mentioned similarly for “titles and abstracts”. Response#9: In the revised manuscript, we explicitly mention the reason for excluding studies.

Comments/Suggestions on Response #6 in R1: Response and revision acceptable.

Comments/suggestions#10: Page-6: Table 1, “Study period” is not mentioned clearly for some of the studies. Need to clearly have a note for this in the table. Wonder, is it due to the missing information in the text.

Response#10: Thank you. Some original studies did not explicitly provided the study period (data collection period).

Comments/Suggestions on Response #10 in R1: Please mention these as a footnote. Indicate with notation ‘*’ in the table text and explain it in the table footnote.

Comments/suggestions#11: Page-7: Author presented the magnitudes of ‘asymptomatic’ COVID-19 cases, wonder if it is included the ‘pre-symptomatic’ cases as well. Need clarification. Accordingly, the title of the manuscript should be revised.

Response#11: Thank you. The outcome of interest (objective) of this study was to estimate the pooled magnitudes of asymptomatic COVID-19 cases throughout the course infection. We will come on that with another article.

Comments/Suggestions on Response #11 in R1: Response and revision acceptable.

Comments/suggestions#12: Page-9: “We also compared the proportion of asymptomatic SARS-CoV-2 infections with previously emerged coronavirus pandemics.” I wonder whether the MERS was a Pandemic. Otherwise, better to be specific by using ‘pandemics/epidemics’ or just simply ‘outbreaks”.

Response#12: Thank you. We restated it.

Comments/Suggestions on Response #12 in R1: Response and revision acceptable.

Comments/suggestions#13 Page-9-10: “The result of this study suggest that contact and symptom based screening might fail to identify all potential SARS-CoV-2 infections.” Author clamed this without any discussion in the main text on it. I would prefer to illustrate this in the discussion section first with the results and then suggest in the conclusion. Conclusion should be related to the results, otherwise take-home massage will be weaker to the readers.

Response#13: Thank you. We already revised it.

Comments/Suggestions on Response #13 in R1: Actually authors has removed the sentence. Response and revision acceptable.

Comments/suggestions#14: Page-9-10: “Scale-up mass testing, which targeting high risk populations is recommended to tackle the pandemic. Continuation of the above points, ‘mass testing’ and ‘testing of the target high risk group’ are two different things. Prefer to revise or rearrange the sentence here. Response#14: Thank you. We already revised it.

Comments/Suggestions on Response #14 in R1: Response and revision acceptable.

Comments/suggestions#15: Many of the references were in preprint now published should be updated. 16. The references are not according to the PloS One specification (“Vancouver” style). Need to be updated.

Response#15: Thank you. We already updated the references according to the PLOS ONE requirement.

Comments/Suggestions on Response #15 in R1: Response and revision acceptable.

Comments/suggestions#16: Finally, I would suggest to the authors to give some effort in the presentation and language of the manuscript to avoid the redundancy of text and improve the language for general readers.

Response#16: Thank you dear reviewer. We try to write the manuscript in acceptable quality of English language.

Comments/Suggestions on Response #16 in R1: Still the text need several improvement in English language, specially in terms of preciseness.

**********

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PLoS One. 2021 Mar 23;16(3):e0249090. doi: 10.1371/journal.pone.0249090.r004

Author response to Decision Letter 1

20 Feb 2021

Author's response to reviews

Title: Magnitude of asymptomatic COVID-19 cases throughout the course of infection: a systematic review and meta-analysis

Author’s email addresses

MA: mulunehadis@gmail.com

LY: lielt.yismaw@gmail.com

MAA: agazhemoges@gmail.com

DBK: danibekele2009@gmail.com

BM: Belaynehmengist2008@gmail.com

BK: bekalukassiedmu@gmail.com

TYB: yemanu.tilahun@gmail.com

Date: 20 February 2021

Dear Editor,

We thank you for the chance to resubmit our revised version of the manuscript. Also, we would like to thank the reviewers for sharing their view and experience. The comments are very important that will improve the manuscript. The point-by-point responses for each of the comments are provided in the following pages. We hope that the revisions meet your standards and that the paper would be published in your journal. We look forward to working with you towards a final published product.

Sincerely,

Muluneh Alene, MPH

On behalf of co-authors

Point by point responses to queries

Reviewer#2

Comments/suggestions #1

Comments/Suggestions on Response #2 in R1: Still text needs to be revised. Please simplify as “Studies vary depending on the number of participants recruited, the type of design employed and the country in which the study conducted.”

Response#1

Dear reviewer thank you so much for your constructive comments. We have revised it.

Comments/suggestions #2

Comments/Suggestions on Response #3 in R1: I was expecting more on motivations here. Specially to indicate why authors took up this study.

Response#2

Thank you. In the revised manuscript, we added more on the motivation of this study.

Comments/suggestions #3

Comments/Suggestions on Response #4 in R1: What are the revision here? It was just a suggestion. If you want to keep the sentence, no problem, still make sense. But could not understand what revision has been made in this context as claimed by author in revised version?

Response#3

Thank you. We keep the sentence as it is.

Comments/suggestions #4

Comments/Suggestions on Response #7 in R1: Still not clear. Authors should not use the subjective term ‘fully’ here. What did the authors mean by ‘fully’?

Response#4

Thanks. We already addressed it.

Comments/suggestions #5

Comments/Suggestions on Response #8 in R1: Not sure, whether I was able to convey the issue to the authors by the comment? Removing the authors’ names were not the suggestion. Here I wanted to know whether two authors had performed the data extraction from the studies included independently or not. Generally, in systematic review and met analysis the two (or more) authors performed such data extraction independently to ensure the reproducibility. Further, how did the authors settled the mismatches? Should be clearly mentioned in the text.

Response#5

Thanks. We have addressed it.

Comments/suggestions #6

Comments/Suggestions on Response #10 in R1: Please mention these as a footnote. Indicate with notation ‘*’ in the table text and explain it in the table footnote.

Response#6

Thanks. We considered your suggestion.

Comments/suggestions #7

Comments/Suggestions on Response #16 in R1: Still the text need several improvement in English language, especially in terms of preciseness.

Response#7

Thank you. In the revised manuscript, we have improved the language of the manuscript using English language professionals.

Thank you!!!

Decision Letter 2

Kin On Kwok

11 Mar 2021

Magnitude of asymptomatic COVID-19 cases throughout the course of infection: a systematic review and meta-analysis

PONE-D-20-28251R2

Dear Dr. Addis,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Kin On Kwok, Ph.D

Academic Editor

PLOS ONE

Acceptance letter

Kin On Kwok

15 Mar 2021

PONE-D-20-28251R2

Magnitude of asymptomatic COVID-19 cases throughout the course of infection: a systematic review and meta-analysis

Dear Dr. Alene:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Kin On Kwok

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. PRISMA 2009 checklist.

    (DOC)

    Click here for additional data file. (64.5KB, doc)
    S1 Table. Individual effect sizes of the included studies conducted on truly asymptomatic SARS-CoV-2 infection, 2020.

    (DOCX)

    Click here for additional data file. (180.3KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (27.7KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.

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